Nueva función para p21 como un modulador de la Síntesis de ADN por translesion

G. SORIA, SPERONI J., BELLUSCIO L, PODHAJCER OL AND GOTTIFREDI V

Carlos Paz - Cordoba

Congreso; 2008, XLIV Reunión Anual / 2008, 44th Annual Meeting; 2008

Sociedad Argentina de Investigaciones Bioquimicas

P21 up-regulation is required to block cell cycle progression after many types of genotoxic insults. In contrast, UV irradiation triggers p21 proteolysis. The biological significance of this increase in p21 turnover is unclear and might be linked to DNA repair-related processes. A few recent reports have addressed its effect on Translesion DNA Synthesis (TLS), a process that avoids prolonged replication blockage during S-phase. Interestingly, we have recently showed that efficient PCNA ubiquitination, a modification of PCNA relevant for TLS, requires p21 degradation. Moreover, p21 was shown to negatively modulate excessive TLS, thus avoiding mutagenesis. In this work we utilize different single cell analysis approaches to study the effect of p21 on TLS. We found that through its PCNA binding domain, p21 inhibited the interaction of the TLS- polymerase, pol0 (pol eta) with PCNA and the assembly of pol0 foci after UV. Moreover, stable expression of a p21 mutant that interferes with pol0 recruitment, without affecting normal DNA replication, induces the accumulation of the damaged-DNA marker, 0H2AX, and increases cell death after UV irradiation. This work presents p21 as the first reported factor capable of negatively modulating pol0 recruitment to DNA-bound PCNA, which indicates that the increased UV- induced degradation of p21 might be critical for efficient TLS.